DK2448950T3 - SYNTHESIS OF N4- (2,2-dimethyl-4 - [(dihydrogen phosphonoxy) methyl] -3-oxo-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4 , 5-trimethoxyphenyl) -2,4-PYRIMIDINDIAMINDINATRIUMSALT - Google Patents
SYNTHESIS OF N4- (2,2-dimethyl-4 - [(dihydrogen phosphonoxy) methyl] -3-oxo-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4 , 5-trimethoxyphenyl) -2,4-PYRIMIDINDIAMINDINATRIUMSALT Download PDFInfo
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- DK2448950T3 DK2448950T3 DK10730679.7T DK10730679T DK2448950T3 DK 2448950 T3 DK2448950 T3 DK 2448950T3 DK 10730679 T DK10730679 T DK 10730679T DK 2448950 T3 DK2448950 T3 DK 2448950T3
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- Prior art keywords
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- amide
- solvate
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- -1 [1,4] oxazin-6-yl Chemical group 0.000 title claims description 12
- 230000015572 biosynthetic process Effects 0.000 title description 14
- 238000003786 synthesis reaction Methods 0.000 title description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title description 7
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 88
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- 239000012453 solvate Substances 0.000 claims description 54
- 150000001408 amides Chemical class 0.000 claims description 52
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 12
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 150000004687 hexahydrates Chemical class 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 150000003511 tertiary amides Chemical class 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910001415 sodium ion Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 150000003334 secondary amides Chemical class 0.000 claims description 2
- LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical group CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 claims 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 230000000087 stabilizing effect Effects 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 22
- 229910019142 PO4 Inorganic materials 0.000 description 20
- 235000021317 phosphate Nutrition 0.000 description 20
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 17
- 239000010452 phosphate Substances 0.000 description 17
- 229910001868 water Inorganic materials 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 12
- 239000003444 phase transfer catalyst Substances 0.000 description 11
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- PJBIHXWYDMFGCV-UHFFFAOYSA-N chloro(chlorosulfonyloxy)methane Chemical compound ClCOS(Cl)(=O)=O PJBIHXWYDMFGCV-UHFFFAOYSA-N 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 150000004677 hydrates Chemical class 0.000 description 5
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 229960004592 isopropanol Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 238000001382 dynamic differential scanning calorimetry Methods 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 125000000547 substituted alkyl group Chemical group 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BHFLSZOGGDDWQM-UHFFFAOYSA-N 1h-benzimidazole;carbamic acid Chemical class NC(O)=O.C1=CC=C2NC=NC2=C1 BHFLSZOGGDDWQM-UHFFFAOYSA-N 0.000 description 1
- 229940123877 Aurora kinase inhibitor Drugs 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000003421 catalytic decomposition reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 238000010943 off-gassing Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
DESCRIPTION I. BACKGROUND OF THE INVENTION Field of the Invention [0001] This invention relates to the field of pharmaceutical/process chemistry. Disclosed herein are methods for synthesizing 2,4- pyrimidinediamines as well as intermediates used therein. As an embodiment, provided herein is a process for preparing N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4- pyrimidinediamine disodium salt (compound of formula I), particularly hydrates (such as a hexahydrate) of the compound of formula I, a 2,4-pyrimidinediamine that is useful in the treatment and prevention of various diseases.
Summary of the Related Art [0002] Various-classes of 2,4-pyrimidinediamine compounds have been discovered that have myriad therapeutic uses. See, for example, U.S. application Ser. No. 10/355,543 filed Jan. 31, 2003 (US 2004/0029902A1), international application Ser. No. PCT/US03/03022 filed Jan. 31, 2003 (WO 03/063794) , U.S. application Ser. No. 10/631,029 filed Jul. 29, 2003 (U.S.2007/0060603), international application Ser. No. PCT/US03/24087 (WO 2004/014382) , U.S. application Ser. No. 10/903,263 filed Jul. 30, 2004 (US2005/0234049), and international application Ser. No. PCT/US2004/24716 (WO/2005/016893).
[0003] One of the process for preparing the 2,4-pyrimidinediamine compounds is described in U.S. Application Ser. No. 11/539,074, filed October 5, 2006.
[0004] WO 2008/064274 discloses prodrugs of biologically active 2,4- pyrimidinediamine compounds, salts and hydrates of the prodrugs, compositions, comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.
[0005] Oslob J D et al. (Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 5, 1 March 2009) discloses water-soluble prodrugs of an aurora kinase inhibitor.
[0006] Chassaing C et al. (Journal Of Medicinal Chemistry, vol. 51, no. 5, 13 March 2008) discloses the synthesis, pharmacodynamics, and pharmacokinetics of highly water-soluble prodrugs of anthelmintic benzimidazole carbamates.
II. SUMMARY OF THE INVENTION
[0007] The invention comprises a processes for preparing N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine disodium salt (compound of formula I): \ f ' inrxø
O N N N N N ^ O
) Η Η T ? 0=lj>-0' Na+ O' Na+
I as well as hydrates (such as a hexahydrate) thereof. The comound of formula I (and hydrates thereof) is a 2,4-pyrimidinediamine that is useful in the treatment and prevention of various diseases. The invention further comprises solvate intermediates useful in the process.
[0008] It will be appreciated by one of skill in the art that the embodiments summarized above may be used together in any suitable combination to generate embodiments not expressely recited above and that such embodiments are considered to be part of the present invention.
III. BRIEF DESCRIPTION OF THE FIGURES
[0009]
Figure 1 illustrates a dynamic differential scanning calorimetry experiment (DSC) in closed cup of neat di-feri-butylchloromethyl phosphate (3.834 mg).
Figure 2 illustrates a Thermo-Graphic-Analysis (TGA) experiment with neat di-feri-butylchloromethyl phosphate (7.7 mg).
Figure 3 illustrates a dynamic differential scanning calorimetry experiment in closed cup of a 36% solution of di-feri-butylchloromethyl phosphate (5.6 mg) in DMAc.
Figure 4 illustrates a isotherm differential scanning calorimetry experiment in closed cup of a 36% di-feri-butylchloromethyl phosphate (10.9 mg) solution in DMAc at 80°C.
IV. DETAILED DESCRIPTION OF THE INVENTION 1. Definitions [0010] As used herein, the following definitions shall apply unless otherwise indicated.
[0011] Unless defined otherwise, all technical, and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.
[0012] "Amide" refers to the group R20CON(R21)2 wherein R20 is selected from hydrogen or optionally substituted alkyl; and each R21 is independently hydrogen or optionally substituted alkyl, or both of R21 and the nitrogen with which they are attached form a 4 to 6 membered aliphatic ring; or R20 and one of the R21 join together with the carbon and nitrogen to which they are attached, respectively, combine to form a 4 to 6 membererd nitrogen containing ring, and the other R21 is hydrogen or optionally substituted alkyl. Amides include primary amides, secondary amides (such as, but not limited to, alkyl formamides and acetamides, such as N-methyl acetamide), and tertiary amides (such as, but not limited to, Ν,Ν-dialkylacetamides, N,N-dialkylformamides, N-alkylpyrrolidones, and N-alkylpiperidones). Particular examples of tertiary amides suitable for use in the presently disclosed solvates include, without limitation N,N-dimethylacetamide, Ν,Ν-dimethylformamide, N-methylpyrrolidinone, N-methylpiperidinone.
[0013] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 8 carbon atoms, such as, 1 to 6 carbon atoms or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). Also by way of example, a methyl group, an ethyl group, an n-propyl, an isopropyl group, a n-butyl group, an isobutyl group, sec-butyl group, and t-butyl are all represented by the term C1-C4 alkyl. Likewise terms indicating larger numerical ranges of carbon atoms are representative of any linear or branched hydrocarbyl falling within the numerical range. This inclusiveness applies to other hydrocarbyl terms bearing such numerical ranges.
[0014] "Base" refers to substance that can accept protons. Examples of bases include, but are not limited to, carbonates, such as cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, hydroxides, such as, sodium hydroxide, potassium hydroxide, lithium hydroxide, and ammonia.
[0015] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[0016] " Solvate" refers to a complex formed by combination of at least one solvent molecule with at least one molecule or ion of the solute. One of ordinary skill in the art will appreciate that the stoichiometry of the solvent to the solute in a solvated may be greater than one, equal to one or less than one. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, acetic acid, Ν,Ν-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When used herein, the term "solvate" is not intended to restrict the solvate compounds described herein to any particular sort of bonding (such as ionic or coordinate covalent bonds).
[0017] The term "substituted," when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
[0018] Substituent groups on optionally substituted alkyls are alkyl, halo, haloalkyl, nitroso, and cyano.
[0019] Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (such as carbon substituted with five groups, i.e., pentavalent carbon). Such impermissible substitution patterns are easily recognized by a person having ordinary skill in the art. 2. Compositions and Process [0020] Disclosed herein are methods for synthesizing 2,4-pyrimidinediamines as well as intermediates used therein. As an embodiment, provided herein is a process for preparing N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine disodium salt (Compound of formula I) (including hydrates thereof, particularly a hexahydrate), a 2,4-pyrimidinediamine that is useful in the treatment and prevention of various diseases.
[0021] The compound of formula I has been described in U.S. Patent No. 7,449,458, filed January 19, 2006. The phosphate containing progroups such as in the compounds of formulae I, II, III, and VI may increase the solubility of the 2,4-pyrimidinediamine compounds that exhibit poor solubility under physiological conditions (for example, solubilities of less than about 10 pg/mL). The phosphate-containing progroups may aid the solubility of the underlying active 2,4-pyrimidinediamine compound, which in turn may increase its bioavailability when administered orally. The phosphate progroups may be metabolized by phosphatase enzymes found in the digestive tract, permitting uptake of the underlying active drug.
[0022] The U.S. Patent No. 7,449,458, filed January 19, 2006, discloses that the water solubility and oral bioavailability of a particular biologically active 2,4-pyrimidinediamine compound, such as compound of formula IV:
IV increased dramatically when formulated to include a progroup at the ring nitrogen atom as in compound of formula II:
II
[0023] Where the water solubility of the compound of formula IV was found to be in the range of about 1-2 pg/mL in aqueous buffer under physiological conditions, the solubility of the corresponding phosphate prodrug (compound of formula II) was found to be greater than 5 mg/mL under the same conditions, or approximately 2000 times greater. This increased water-solubility allows for better dissolution in the gut, thereby facilitating oral administration.
[0024] A process for preparing the compound of formula I has been described in U.S. Application Ser. No. 11/539,074, filed October 5, 2006, vtfiich is incorporated herein by reference in its entirety in the present disclosure.
[0025] The invention includes a process for preparing a compound of formula I:
1 comprising: 1. a) contacting an acid solvate of a compound of formula II:
IT with an amide under conditions suitable for forming an amide solvate of the compound of formula II; and 2. b) contacting the amide solvate with an aqueous base comprising sodium ions under conditions suitable for forming the compound of formula I. In a particular embodiment, the compound of formula I is a hydrate, such as a hexahydrate.
[0026] In some embodiments, the acid solvate of the compound of formula II is a carboxylic acid. In some embodiments, the carboxylic acid is R1COOH wherein R1 is -H or a C1-C4 alkyl optionally substituted with up to three halo substituents.
[0027] In another aspect the invention comprises the novel amide solvate intermediate of formula III:
III
[0028] The amide solvate III can be synthesized by conversion of an acid solvate of the compound for formula II to the amide solvate III. One of ordinary skill in the art will recognize in view of the present disclosure that the amide solvates of formula III can be made via other forms of II, not only acid solvates of II. In some embodiments, the conditions suitable for forming the amide solvate of the compound of formula II comprise contacting the acid solvate with the tertiary amide at a temperature of between about 20 °C and about 50 °C. In some embodiments, the conditions suitable for forming the amide solvate comprise re-slurrying the acid solvate in Ν,Ν-dimethyl formamide (DMF) at a temperature of about 40 °C.
[0029] In some embodiments, the aqueous base in step b) above comprises sodium hydroxide (NaOH) and an alcohol, and the conditions suitable for forming the compound of formula I comprise a temperature of between about 40 °C about 80 °C and a pH of about 9 to about 10.5. In some embodiments, the alcohol includes, but is not limited to, methanol, ethanol, iso-propanol, butanol, t-butanol, pentanol.
[0030] In some embodiments, the aqueous base in step b) above comprises sodium hydroxide (NaOH) and isopropyl alcohol (IPA), and the conditions suitable for forming the compound of formula I comprise a temperature of about 80 °C and a pH of about 10.2.
[0031] In another aspect, the invention comprises a process for preparing a precursor (VI) of the compound of formula I:
I comprising contacting a compound of formula IV:
IV with a compound of formula V:
V in the presence of an amide, wherein: R3 and R4 are each independently C-|-C6 alkyl; and Xis halogen; under conditions suitable for forming a compound of formula VI:
VI
[0032] In another embodiment, the invention comprises a method of converting the precursor VI into the compound of formula I, the method comprising: 1. a) contacting the compound of formula VI with an acid under conditions suitable for forming an acid solvate of a compound of formula II:
II 2. b) contacting the acid solvate of the compound of formula II with an amide under conditions suitable for forming an amide solvate of the compound of formula II; and 3. c) contacting the amide solvate of the compound of formula II with an aqueous base comprising sodium ions under conditions suitable for forming the compound of formula I.
In a particular embodiment, the compound of formula I produced by this method is a hydrate, such as a hexahydrate.
[0033] In another embodiment, the invention comprises the sequential combination of the two previous methods (i.e., a method comprising the method of making precursor VI followed by the method of converting VI to the compound of formula I).
[0034] In some embodiments, the compound of formula V is di-fert-butyl chloromethyl phosphate:
[0035] The conditions suitable for producing the compound of formula VI can comprise: 1. (i) combining the compound of formula IV with the compound of formula V with a base in a polar solvent; and 2. (ii) washing the product obtained from step (i) in an aqueous base solution.
[0036] Examples of bases suitable for use in steps (i), (ii) or both include, but are not limited to, carbonates, such as cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, hydroxides, such as, sodium hydroxide, potassium hydroxide, lithium hydroxide, and 1°, 2° and 3° amines such as triethylamine, N,N-dimethylaniline, Ν,Ν-diethylaniline and ammonia, as well as metal alkoxides e.g. potassium t-butoxide.
[0037] Examples of polar solvent include, but are not limited to, Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylsulfoxide. Mixtures of such solvents also can be used as is known to those of skill in the art. Moreover, those of skill in the art also would understand that such polar solvents can include non-polar components in a mixture with one or more polar solvents so long as the resultant solvent mixture is polar. Solvents typically considered to be polar include those having a dielectric constant, ε, of at least about 5 and typically greater than about 7 or 8. For example, tetrahydrofuran has a dielectric constant, ε of 7.6, whereas DMF has a dielectric constant of 37.
[0038] In some embodiments, the base in step (i) above comprises at least one of cesium carbonate (CS2CO3) and potassium carbonate (K2CO3); the polar solvent comprises at least one of DMF and Ν,Ν-dimethylacetamide (DMAc); and the aqueous base in step (ii) above comprises at least one of sodium bicarbonate (NaFIC03) and sodium hydroxide (NaOH).
[0039] In some embodiments, the compound of formula VI is not isolated.
[0040] In some embodiments, the compound of formula V is stabilized with Ν,Ν-dimethylacetamide (DMAc) solvent.
[0041] Generally, the compound of formula V, such as, di-ferf-butyl chloromethyl phosphate, is an unstable product. As an example, di-ferf-butyl chloromethyl phosphate undergoes decomposition upon storage to give off heat and iso-butene gas. With reference to the scheme below, and while not intending to be bound by theory, it is believed that the presence of trace amounts of acid catalyzes the cleavage of an O-ferf-butyl group on di-ferf-butyl chloromethyl phosphate A to give mono-ferf-butyl species C with the release of isobutene. Species C can act as an acid source further driving autocatalytic decomposition to phosphate E. As indicated by the dotted line in the scheme below, phosphate E can also provide protons to feed into the autocatalytic decomposition of A Decomposition of A is exothermic and produces two moles of isobutene per mole of A.
[0042] When stored under adiabatic conditions, the heat and pressure build-up from decomposition can be significant. Figure 1 illustrates that storage of di-ferf-butyl chloromethyl phosphate under adiabatic conditions can result in decomposition whereby the pressure and temperature increase dramatically. Figure 1 illustrates a dynamic differential scanning calorimetry experiment (DSC) in closed cup of neat di-ferf-butylchloromethyl phosphate (heating from 0 °C to 300 °C at a rate of 5 °C/min under a N2 flow of 50 mL/min.). Referring to Figure 1, after an endothermic signal (start of isobutene release under upon formation of acidic by products; extrapolated peak at 99.10 °C with a peak width of 0.33 °C and an integrated area of -108.45 mJ) a very sharp exothermic signal at about 100°C is observable (extrapolated peak at 100.57 °C with a peak width of 3.99 °C and a integrated area of 2717.05 mJ), which is typical for an autocatalytic decomposition. Figure 2 illustrates a Thermo-Graphic-Analysis (TGA) experiment with neat di-ferf-butylchloromethyl phosphate, showing that continuous decomposition is observed with isobutene offgassing. In Figure 2, the sample was heated from 20 °C to 300 °C at a rate of 5 °C/min under N2 at a flow rate of 80 mL/min. The sample showed a 41.465% (3.189 mg) mass loss between about 21 °C and 119 °C; and a 19.526 % (1.502 mg) mass loss between about 119 °C and 300 °C. Most of the isobutene is sharply split off at 110°C; after 1 h at 300°C the weight of the sample corresponds to acid E as depicted above. Further tests have shown the pressure increase due to isobutene release can be as great as 80 bar. Also, isobutene is a flammable gas therefore venting large quantities of iso-butene can be dangerous.
[0043] Therefore, it is normally critical to design equipment for the storage of the compound of formula V that can withstand the pressure build up. Various other safety measures need to be taken as well, such as temperature control, distillation time, and safety valve dimension, to avoid equipment damage during the unwanted decomposition reaction.
[0044] However, it was unexpectedly found that the addition of Ν,Ν-dimethylacetamide (DMAc) stabilizes di-ferf-butyl chloromethyl phosphate such that the compound may be stored at about 60°C with no autocatalytic decomposition and no gas being formed (see Figures 3-4). Figure 3 illustrates a dynamic differential scanning calorimetry experiment in closed cup of a 36% solution of di-ferf-butylchloromethyl phosphate in DMAc (heating from 0 °C to 300 °C at a rate of 5 °C/min. under a N2 flow of 50 mL/min.). After an endothermic signal (some isobutene loss due to trace acid; extrapolated peak at 116.42 °C with a peak width of 6.19 °C and an integrated area of -70.78 mJ) a smooth exothermic signal at 120°C is observable (no sharp exothermic signal at 99 to 100°C is observable; extrapolated peak at 129.74 °C with a peak width of 42.52 °C and an integrated area of 1362.40 mJ). This indicates that the system is not undergoing autocatalytic decomposition. Figure 4 illustrates an isothermic differential scanning calorimetry (DSC) experiment in closed cup of a 36% di-ferf-butylchloromethyl phosphate solution in DMAc at 80°C (under a N2 flow of 50 mL/min.). No endothermic or exothermic decomposition of a 36% di-ferf-butylchloromethyl phosphate solution in DMAc is observed at storage temperatures (45, 60 and even 80°C) over 15 hours, thus the di-ferf-butylchloromethyl phosphate is stabilized. In fact, isothermal heating at 60°C of a solution from 68.7g of a 36% solution of di-ferf-butylchloromethyl phosphate in DMAc for over 96 hours generated no gas (isobutene).
[0045] It is to be understood that any amide, such as, but not limited to, DMAc, may be used to stabilize the compound of formula V, including di-ferf-butyl chloromethyl phosphate. Such amides are well known to a person of ordinary skill in the art. Examples of such amides include, but are not limited to, Ν,Ν-dimethylacetamide, Ν,Ν-dimethylformamide, N-methylpyrrolidinone. In some embodiments, a solvent may be optionally added to a combination of the amide and di-ferf-butyl chloromethyl phosphate. In some embodiments, the amide may also be a solvent. For example, DMAc can be used as the amide as well as the solvent.
[0046] Accordingly, in one aspect, there is provided a composition consisting essentially of di-fert-butyl chloromethyl phosphate:
and an amide optionally in a solvent.
[0047] In some embodiments, the amide is also the solvent.
[0048] In some embodiments, the amide is a tertiary amide.
[0049] In some embodiments, the tertiary amide is Ν,Ν-dimethylacetamide (DMAc).
[0050] The improved process for the synthesis of the compound of formula I is as illustrated in Schemes l-VII below. 3. Synthetic Schemes [0051] Starting materials used in the synthesis described herein are available commercially. The synthesis of the compound of formula V is as shown in Scheme I below:
Scheme I
[0052] According to Scheme I, compound of formula V is obtained by the reaction of potassium dialkyl phosphate group (R3 and R4 as defined hereinabove) with an alkylating agent (X as defined hereinabove), such as a halomethylchlorosulfate in the presence of a phase transfer catalyst (PTC). Numerous examples of phase transfer catalysts are known to those of skill in the art. Examples of such phase transfer catalysts include, without limitation tetraalkyl ammonium salts, such as tetrabutyl ammonium salts. For example, di-ferf-butyl chloromethyl phosphate can be obtained by the reaction of potassium or sodium di-ferf-butyl phosphate (PDP) with chloromethylchlorosulfate (CMCS) in the presence of tetrabutylamonium bisulfate (TBAHS).
[0053] Scheme la below (as well as Figures 1-4 and the Examples below), shows that the pH adjustment and the addition of N,N-dimethylacetamide (DMAc) stabilizes di-ferf-butyl chloromethyl phosphate such that the compound may be kept at about 60°C with no gas being formed.
Scheme la
[0054] It is to be understood that the synthesis of di-ferf-butyl chloromethyl phosphate in Scheme la is for illustration purposes only. Synthesis of other phosphates of the compound of formula V by following Scheme la can be carried out by routine adaptation of the method. In addition, sodium or other salts of di-ferf-butyl phosphate and other reaction conditions can be used to make di-ferf-butyl chloromethyl phosphate.
[0055] The synthesis of the compound of formula Via from compound of formula IV is as illustrated in Scheme II below:
Scheme IT
A
[0056] According to Scheme II, the compound of formula IV is treated with di-ferf-butyl chloromethyl phosphate to result in the compound of formula Via (such as step B of Example 1 herein). It is to be understood that reaction of a compound of formula IV with di-ferf-butyl chloromethyl phosphate is for illustration purposes only. Other phosphates, such as compound of formula V described herein, may be reacted with the compound of formula IV to result in the compound of formula VI using routine adaptation of the method. The steps described further below for the compound of formula Via may also be applied to the compound of formula VI.
[0057] In some embodiments, CS2CO3 as a base and DMAc as the solvent in the synthesis of the compound of formula Via. Base CS2CO3 may be substituted with K2CO3 or KOtBu, each alone or in combination with each other or CS2CO3. The compound of formula Via can be isolated as a solid but can also be obtained as solution in methyl fert-butyl ether (MtBE).
[0058] Synthesis of the acid solvate of the compound of formula II from a compound of formula Via is as illustrated in Scheme III and exemplified in step C of Example 1 below:
Scheme III
acid solvate [0059] According to Scheme III, the compound of formula Via is dissolved in a mixture of an acid R1-COOH (R1 is as defined hereinabove) and water and heated to about 55-70°C. For example, as described in step C of Example 1, the compound of formula Via is dissolved in acetic acid and water (4:1 Ac0H:H20) and heated to 67°C to yield an acetic acid solvate of the compound of formula II.
[0060] The synthesis of the amide solvate of the compound of formula II from the acid solvate of the compound of formula II is as illustrated in Scheme IV and exemplified in step C of Example 1:
Scheme IV
1 wherein the compound of formula I is optionally in the form of a hydrate, such as a hexahydrate.
[0061] The conversion of the acid solvate of the compound of formula II to the amide solvate of the compound of formula II comprises reslurrying the acid solvate of the compound of formula II in a tertiary amide, such as R^CON(R^)2 (where R^ and R^ are as defined hereinabove) between about 20°C-50°C. For example, as described in step C of Example 1, the acetic acid solvate of the compound of formula II is reslurried in DMF at about 40°C to yield a DMF solvate of the compound of formula II.
[0062] This step of reslurrying of the acid solvate to obtain the DMF solvate of the compound of formula II results in a higher quality product with less starting material and byproducts, such as, depletion of the compound of formula IV to < 1 mole % and of p-dimer to < 0.1 mole %. The product is stable at 40°C for about 24h. This improved process results in improved filterability of the product. This improved process further results in increased yield by about 10%.
[0063] A synthesis of the compound of formula I from the amide solvate of the compound of formula II is as exemplified in step D of Example 1. The amide solvate of the compound of formula II is taken in an alcohol, such as, isopropylalcohol/water where the pH is adjusted between about 9 to about 10.5 by adding a base, such as, NaOFI. The solution is heated between about 40°C to about 80°C. In one embodiment, the DMF solvate of the compound of formula II is treated with isopropylalcohol/water at a temperature of about 80°C and a pH of about 8 - 10.2 to result in the compound of formula I.
IV. EXAMPLES
[0064] The invention is further understood by reference to the following examples, which are intended to be purely exemplary of certain aspects of the invention and are not intended to limit the scope.
[0065] In the examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings. cm = centimeter
CMOS = chloromethylchlorsulfate CS2CO3 = cesium carbonate
DCM = dichloromethane DM Ac = dimethylacetamide h
= hours HCI
= hydrochloric acid IPA = isopropylalcohol mbar = millibar
MeOH = methanol
MtBE = methyl- ferf-butyl ether mol
= molar mL = milliliter 9 = gram mg = milligram rpm = revolutions per minute min = minute mm
= millimeter N = normal Na2CC>3 = sodium carbonate NaHCC>3 = sodium bicarbonate
NaOH = sodium hydroxide
NMP = N-methylpyrrolidinone
NMR = nuclear magnetic resonance
PDP = di-f-butylphosphate
PTC
= phase transfer catalyst TBAHS = tetrabutylamoniumhydrogehsulfate v/v = volume/volume
°C = degree Celsius POCI3 = Phosphorus oxychloride Example 1 A. Preparation of di-ferf-butyl chloromethyl phosphate:
Procedure I:
Preparation of stabilized di-ferf-butyl chloromethyl phosphate [0066] Preparation of di-ferf-butyl chloromethyl phosphate, has been described in the literature, such as in Mantyla, et al. Tetrahedron Letters, 43(2002), 3793-3794 and Chadwick, et al. US 2006/0047135. We have found improvements to these processes whereby the yield is increased, with high purity, and the di-ferf-butyl chloromethyl phosphate is stabilized via exposure to an amide. The specific example below illustrates this aspect of the invention.
[0067] Surprisingly, it was found that di-ferf-butyl chloromethyl phosphate could be synthesized in excellent yield (>90%) and purity (>99%) by dosing 2.5 eq. CMCS to a two phase mixture of PDP and phase transfer catalyst TBAHS in DCM/water and adjusting pH value to 8 at the same time by addition of 20% aqueous NaOH. Additionally it was found, that the stability of di-ferf-butyl chloromethyl phosphate was tremendously enhanced and no auto catalytic decomposition behaviour was observed by preparation of a 30 w% solution in dimethylacetamide (DMAc).
Description of the process: [0068] Di-fert-butyl chloromethyl phosphate was synthesized using a TBAHS phase transfer catalysed reaction of PDP in DCM/H2O with 2.5 eq. CMCS at 18°C. The pH was monitored and adjusted to 8 by addition of 20% aqueous NaOH.
[0069] The DCM was removed at 20°C and a pH > 7 at reduced pressure (recycling of DCM). To the crude di-fert-butyl chloromethyl phosphate was added MtBE, and the TBASHS was removed by washing the MtBE layer with 2% aqueous bicarbonate solution. To stabilize the di-fert-butyl chloromethyl phosphate, DMAc was added, and then the MtBE was distilled off.
The yield was > 90% based on PDP starting material. The purity of di-fert-butyl chloromethyl phosphate in DMAc according to 1H- NMR> 99% [0070] This procedure has at least the following advantages: 1) a liquid base (aqueous NaOH) instead of an excess of solid base such as NaHC03, Na2HP04 or Na2C03 can be used; 2) the reaction can be performed in a more concentrated state because an excess of less soluble bicarbonates or phosphates are replaced by soluble chlorides, thereby minimizing volume requirements and reaction time while improving yield. Also, the stability of the di-fert-butyl chloromethyl phosphate is enhanced, up to 40°C, by preparation of, for example, a 30 w% solution in DMAc.
[0071] In a specific example, 56.3 g of PDP (1.0 mol equivalent: 91.2 w%) was mixed with 3.53 g of TBAHS (0.05 eq.), 60 g of water and 300 g of DCM. At room temperature, 86.6 g of CMCS (2.5 eq.) was dosed to the reaction mixture over 4 h. During the dosing of CMCS, the pH was adjusted to 8 by addition of 227 g of 20% aqueous NaOH. The resulting two phase reaction mixture was stirred overnight at 20°C. The DCM was distilled off at 20°C under reduced pressure (500—»300 mbar) from the two phase mixture. After addition of 200 mL MtBE to the residue, layers were separated. The water layer was discarded and the organic layer was washed once with 300 mL 2% aqueous NaHC03 to remove phase transfer catalyst. After addition of 90 mL DMAc, MtBE was distilled off at 40°C and reduced pressure. Liquid nitrogen was bubbled through the resulting mixture for 1 hour to remove traces of DCM and MtBE. The di-fert-butyl chloromethyl phosphate (128 g of an oil) was obtained and analysed by 1H-NMR, showing a yield of di-fert-butyl chloromethyl phosphate of 90.7%. (di-fert-butyl chloromethyl phosphate: 36.4%; DMAc: 63.4 w%; DCM: 0.03 w%; MtBE: 0.01 w%; PTC: 0.01 w%; Water: 0.6 w%).
[0072] Additional advantages include: 1) DCM can be recycled, 2) PTC can be removed in a single extraction, 3) only 5 mol% of PTC is needed, and 4) all but minute traces of DCM and MtBE are remove by bubbling N2.
B. Preparation of compound of formula Via in MtBE
[0073]
Description of synthesis of compound of formula Via: [0074] Cesium carbonate, 27.3 g (1.2 eq.), 185 g of N,N-Dimethylacetamide, 33.5g of compound of formula IV (1 eq., 70mmol) and 74g of 30.6w% di-fert-butyl chloromethyl phosphate (1.25 eq.) in DMAc were charged and stirred at 40°C overnight. A beige suspension resulted. The suspension was cooled to room temperature and 118mL each of MTBE and water were added. The phases were separated and the aqueous layer washed with 94mL MTBE. The organic layers were each washed with 94mL water. The organic layers yielded 187.9 g of compound Via in MTBE, (yield 74% based on 70 mmol compound of formula IV). C. Preparation of compound of formula lla (amide solvate): [0075]
Description: [0076] Acetic acid (168.6 g, 160.6mL) was combined with an equal amount of water and the mixture heated to 67°C. The compound of formula Via (187g, 170mL) of the solution in MTBE obtained as described above was added to the aqueous acetic acid. Most of the MTBE was distilled off at atmospheric pressure and the resulting solution stirred for 2h, resulting in a yellow suspension. The remaining MTBE was distilled off at 300mbar and the suspension cooled to 20°C and filtered to give an off-white solid. The filter cake was washed with cold acetone (2 x 160 mL) and dried overnight at 30°C to yield 29.8 g of the compound of formula II as an acetic acid solvate.
[0077] A suspension of 29.8 g of the compound of formula II as an acetic acid solvate at or about 1:1 stoichiometry) and 150mL DMF were heated to 50°C and stirred for 2 h. The suspension was then cooled to room temperature and filtered. The filter cake was washed three times with 98 mL of MTBE and dried under vacuum overnight at 30°C. The amide solvate of the compound of formula II (26.7g) was obtained (yield 55% based on 70 mmol of compound IV). D. Preparation of a hexahydrate of the compound of formula I: [0078] The amide solvate (10 g, 15 mmol) was suspended in 100 mL water and stirred for 1 hour. Subsequently, 50 mL IPA were added and the pH was adjusted from 3.3 to 8.5 by addition of 31.9 g of 1M NaOH. The reaction mixture was heated to 82°C, stirred for 1 hour, filtered through a 10 micron filter, cooled to 20°C, and stirred over night. The resulting suspension was filtered and the filter cake washed twee wth 40 mL acetone and dried under vacuum over night at 40°C to give 8.6 g of a hexahydrate of the compound of formula I (77% yield).
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • US355S4303A [00021 • US20040029902Å1 ;0002t • .WO03063794A [0002] • US63102903A [8002] • US20070030603A :00021 • US0324087W [0002] . WQ20040t4382A [00021 • USS0326304A [0002] • US20050234Q49A [0002] • US200424716W [00021 • VV02005016893A [0002] • W0200S064274A [0004] • US20060047135A ΓΟΟββ]
Non-patent literature cited in the description • OSLOB J D et al.Bioorganic & Medicinal Chemistry Letters, 2009, vol. 19, 5 £00051 • CHASSAING C et al.Journal Of Medicinal Chemistry, 2008, vol. 51,5 [0006] • MANTYLAet al.Tetrahedron Letters, 2002, vol. 43, 3793-3794 [0066]
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Applications Claiming Priority (2)
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| US27007309P | 2009-07-02 | 2009-07-02 | |
| PCT/US2010/040792 WO2011002999A1 (en) | 2009-07-02 | 2010-07-01 | Synthesis of n4- (2, 2-dimethyl-4- [ (dihydrogen phosphonoxy ] -3-oxo-5-pyrido [1, 4] oxazin-6-yl)-5-fluoro-n2- (3, 4, 5,-trimethoxyphenyl) -2, 4- pyrimidinediamine disodium salt |
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| WO2008009122A1 (en) | 2006-07-20 | 2008-01-24 | Affinium Pharmaceuticals, Inc. | Acrylamide derivatives as fab i inhibitors |
| UA108077C2 (en) | 2009-07-02 | 2015-03-25 | SYNTHESIS OF DINODIUM SALT N4- (2,2-DIMETHYL-4 - $ (DYHYDROPHOPHONOXY) METHYL] -3-OXO-5-PYRIDO $ 1,4] OXAZIN-6-YL) -2-FLUORINE 5-TRIMETHOXYPHENYL) -2,4-PYRIMIDINDIAMINE | |
| CA2790199A1 (en) * | 2010-02-24 | 2011-09-01 | Auspex Pharmaceuticals, Inc. | Trimethoxyphenyl inhibitors of tyrosine kinase |
| WO2013014454A1 (en) | 2011-07-28 | 2013-01-31 | Astrazeneca Ab | New (trimethoxyphenylamino)pyrimidinyl formulations |
| TWI526437B (en) * | 2011-09-09 | 2016-03-21 | 台灣神隆股份有限公司 | Crystalline forms of cabazitaxel |
| US8426450B1 (en) * | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| SMT201900411T1 (en) | 2012-06-19 | 2019-09-09 | Debiopharm Int Sa | Prodrug derivatives of (e)-n-methyl-n-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide |
| CN102746337B (en) * | 2012-06-21 | 2014-12-17 | 成都苑东药业有限公司 | 2,4-pyrimidinediamine compound and preparation method thereof |
| US9145411B2 (en) | 2012-08-02 | 2015-09-29 | Asana Biosciences, Llc | Substituted amino-pyrimidine derivatives |
| PT3083648T (en) * | 2013-12-20 | 2018-12-14 | Rigel Pharmaceuticals Inc | PHARMACEUTICAL AND INTERMEDIATE PROCESS |
| SMT202000719T1 (en) | 2016-02-26 | 2021-03-15 | Debiopharm Int Sa | Medicament for treatment of diabetic foot infections |
| US20180065992A1 (en) | 2016-09-08 | 2018-03-08 | Glykon Technologies Group, Llc | Monomeric bimetal hydroxycitric acid compounds and methods of making and using the same |
| WO2019070827A1 (en) * | 2017-10-04 | 2019-04-11 | Celgene Corporation | Processes for the preparation of cis-4 [2-{(3s.4r)-3-fluorooxan-4-yl]amino)-8-(2,4,6-trichloroanilino)-9h-purin-9-yl]-1-methylcyclohexane-1-c arboxamide |
| HUE062061T2 (en) | 2019-02-14 | 2023-09-28 | Debiopharm Int Sa | Afabicin formulation, method for making the same |
| UA129222C2 (en) | 2019-06-14 | 2025-02-12 | Дебіофарм Інтернешнл С.А. | Afabicin for use for treating bacterial infections involving biofilm |
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| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| US20040024716A1 (en) | 2002-04-12 | 2004-02-05 | James Malatesta | Mail sorting processes and systems |
| RS51752B (en) | 2002-07-29 | 2011-12-31 | Rigel Pharmaceuticals | METHODS OF TREATMENT AND PREVENTION OF AUTOIMMUNE DISEASES WITH 2,4-PYRIMIDINDIAMINE COMPOUNDS |
| HRP20130602T1 (en) | 2003-07-30 | 2013-07-31 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases |
| US20060047135A1 (en) | 2004-08-30 | 2006-03-02 | Chadwick Scott T | Process for preparing chloromethyl di-tert-butylphosphate |
| DE602006010979D1 (en) * | 2005-01-19 | 2010-01-21 | Rigel Pharmaceuticals Inc | PRODRUGS FROM 2,4-PYRIMIDIN DIAMIN COMPOUNDS AND THEIR USES |
| US20090114877A1 (en) * | 2005-09-13 | 2009-05-07 | Eisai R&D Management Co., Ltd. | Composition Containing Stability-Improved Chloromethyl Phosphate Derivatve and Process for Producing Same |
| US8163902B2 (en) * | 2006-11-21 | 2012-04-24 | Rigel Pharmaceuticals, Inc. | Prodrugs of 2,4-pyrimidinediamine compounds and their uses |
| UA108077C2 (en) | 2009-07-02 | 2015-03-25 | SYNTHESIS OF DINODIUM SALT N4- (2,2-DIMETHYL-4 - $ (DYHYDROPHOPHONOXY) METHYL] -3-OXO-5-PYRIDO $ 1,4] OXAZIN-6-YL) -2-FLUORINE 5-TRIMETHOXYPHENYL) -2,4-PYRIMIDINDIAMINE |
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| CA2766801A1 (en) | 2011-01-06 |
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| RS54679B1 (en) | 2016-08-31 |
| JP2012532143A (en) | 2012-12-13 |
| CY1117489T1 (en) | 2017-04-26 |
| US20130274499A1 (en) | 2013-10-17 |
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